The objective of Project 2 is to develop PET and SPECT radioligands with low lipophilicity and high affinity for quantifying CB1 receptors in the living human brain. This receptor is the binding site in brain of endocannabinoid molecules involved in signaling pathways, and for A9 tetrahydrocannabinol (THC), the active principle of marijuana. All known cannabinoid receptor ligands have high logP values, and although it is a very imperfect proxy, high values of this parameter are associated with poor brain uptake. In previous work, we developed radioiodine-labeled AM281, an antagonist/inverse agonist pyrazole radioligand with moderate lipophilicity and affinity. Although suboptimal because of low brain uptake and rapid clearance, SPECT studies with AM281 have established that the CB1 receptor can be studied in the living human brain using radionuclide tomography. The sensitivity of PET scanners is about ten times that of SPECT scanners, thus an 18F or 11C radioligand with similar uptake and clearance properties to AM281 is anticipated to be very useful for clinical research. For SPECT, it is necessary to develop a radioligand with equivalent or greater brain penetration than AM281, but with subnanomolar affinity, so that its accumulation from the blood by binding to receptor in brain could continue for a longer period of time, and thus reach a higher "equilibrium" level of binding. The relatively long half-life (13.2 h) of 123Ipermits imaging for long periods, and this, together with prolonged uptake and slow clearance, can compensate for SPECT's inherent insensitivity, compared with PET. In the present application we propose to radiolabel and evaluate compounds developed in Project 1 as PET or SPECT tracers in a mouse model. Studies will involve screening compounds for brain uptake using liquid chromatography/mass spectrometry, as well as microdissection and autoradiographic experiments with radiolabeled compounds. For promising compounds the labeling will be translated to PET or SPECT nuclides for primate imaging studies. Relevance to public health: Imaging studies would allow evaluation of disease and drug induced changes in cannabinoid receptor densities in various regions of the human brain, and contribute not only to our understanding of the neural basis of marijuana abuse, but also to medication development, since both agonists and inverse agonists/antagonists of the CB1 receptor have medicinal potential.